Studies supported by the SPORE during the initial funding period demonstrated that immunostimulatory CpG ODN and IL-21 are synergistic in their ability to induce apoptosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) cells. One of the mechanisms responsible for this apoptosis is production of Granzyme B by the malignant B cells - a surprising finding given that B cells have not previously been shown to produce Granzyme B. IL-21 plus anti-B cell receptor antibody (Anti-BCR) also induce Granzyme B production by both CLL cells and other B cell populations. The identification of a potentially powerful new mechanism of anti-tumor activity opens up a number of new avenues for investigation. Studies are proposed to explore the mechanisms responsible for induction of Granzyme B production by the B cells, how cells treated in such a manner mediate anti-tumor activity, and how such activity can be utilized therapeutically. Specifically, the effects of IL-21, CpG ODN, and anti-BCR, alone and in combination, on malignant and benign B cells will be determined to define the molecular changes induced by therapy and correlate these changes with the effect of therapy on malignant B cell viability and phenotype. The relative importance of autolysis, undirected cytotoxicity and antibody directed cellular cytotoxicity (ADCC) in the apoptosis of malignant B cells treated with these agents will be determined. Studies will assess how malignant B cells respond to other combinations of B cell activating agents. In the clinic, correlative studies will be done in conjunction with an ongoing phase I trial of CpG ODN in CLL to assess whether in vivo therapy with CpG ODN induces changes in CLL cells similar to those observed in vitro. Studies will be done to evaluate how clinical therapy with CpG ODN impacts on the response of CLL cells to IL-21, and other biological agents in vitro. Additional clinical trials of combinations of biologically active agents in CLL or other B cell malignancies will be tested based on the initial preclinical and clinical results. These studies, which will make extensive use of all of the SPORE shared resources, will provide valuable information on how the unexpected immunologic finding that B cells can produce functional Granzyme B, can be applied to the treatment of Lymphoma and other B cell malignancies.